The ecteinascidins (herein abbreviated Et or Et""s) are exceedingly potent antitumor agents isolated from the marine tunicate Ecteinascidia turbinata. Several ecteinascidins have been reported previously in the patent and scientific literature. See, for example:
U.S. Pat. No. 5,721,362, which describes a synthetic process for the formation of ecteinascidin compounds and related structures, such as the saframycins. In one particularly preferred embodiment, the patent provides a synthetic route for the formation of ecteinascidin 743, an exceedingly potent marine-derived antitumor agent, now in clinical trials. The process of this patent is enantio- and stereocontrolled, convergent and short. Also disclosed are novel process intermediates, useful not only in the total synthesis of ecteinascidin 743, but also other known ecteinascidin compounds, including derivatives and analogs thereof.
U.S. Pat. No. 5,256,663, which describes pharmaceutical compositions comprising matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata, and designated therein as ecteinascidins, and the use of such compositions as antibacterial, anti-viral, and/or antitumor agents in mammals.
U.S. Pat. No. 5,089,273, which describes novel compositions of matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata, and designated therein as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and/or antitumor agents in mammals.
U.S. Pat. No. 5,478,932, which describes ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo protection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX-1 human lung and MX-1 human mammary carcinoma zenografts.
U.S. Pat. No. 5,654,426, which describes several ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo protection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX-1 human lung and MX-1 human mammary carcinoma zenografts.
See also: Corey, E. J., J. Am. Chem. Soc., 1996, 118 pp. 9202-9203; Rinehart, et al., Journal of National Products, 1990, xe2x80x9cBioactive Compounds from Aquatic and Terrestrial Sourcesxe2x80x9d, vol. 53, pp. 771-792; Rinehart et al., Pure and Appl. Chem., 1990, xe2x80x9cBiologically active natural productsxe2x80x9d, vol. 62, pp. 1277-1280; Rinehart, et al., J. Org. Chem., 1990, xe2x80x9cEcteinascidins 729, 743, 745, 759A, 759B, and 770: Potent Antitumor Agents from the Caribbean Tunicate Ecteinascidia turbinataxe2x80x9d, vol. 55, pp. 4512-4515; Wright et al., J. Org. Chem., 1990, xe2x80x9cAntitumor Tetrahydroisoquinoline Alkaloids from the Colonial Ascidian Ecteinascidia turbinataxe2x80x9d, vol. 55, pp. 4508-4512; Sakai et al., Proc. Natl. Acad. Sci. USA 1992, xe2x80x9cAdditional antitumor ecteinascidins from a Caribbean tunicate: Crystal structures and activities in vivoxe2x80x9d, vol. 89, 11456-11460; Science 1994, xe2x80x9cChemical Prospectors Scour the Seas for Promising Drugsxe2x80x9d, vol. 266, pp. 1324; Koenig, K. E., xe2x80x9cAsymmetric Synthesis,xe2x80x9d ed. Morrison, Academic Press, Inc., Orlando, Fla., vol. 5, 1985, p. 71; Barton, et al., J. Chem Soc. Perkin Trans., 1, 1982, xe2x80x9cSynthesis and Properties of a Series of Sterically Hindered Guandidine Basesxe2x80x9d, pp. 2085; Fukuyama et al., J. Am Chem Soc., 1982, xe2x80x9cStereocontrolled Total Synthesis of (+)-Saframycin Bxe2x80x9d, vol. 104, pp. 4957; Fukuyama et al., J. Am Chem Soc., 1990, xe2x80x9cTotal Synthesis of (+)-Saframycin Axe2x80x9d, vol. 112, p. 3712; Saito, et al., J. Org. Chem., 1989, xe2x80x9cSynthesis of Saframycins. Preparation of a Key Tricyclic Lactam Intermediate to Saframycin Axe2x80x9d, vol. 54, 5391; Still, et al., J. Org. Chem., 1978, xe2x80x9cRapid Chromatographic Technique for Preparative Separations with Moderate Resolutionxe2x80x9d, vol. 43, p. 2923; Kofron, W. G.; Baclawski, L. M., J. Org. Chem., 1976, vol. 41, 1879; Guan et al., J. Biomolec. Struc. and Dynam., vol. 10 pp. 793-817 (1993); Shamma et al., xe2x80x9cCarbon-13 NMR Shift Assignments of Amines and Alkaloids,xe2x80x9d p. 206 (1979); Lown et al., Biochemistry, 21, 419-428 (1982); Zmijewski et al., Chem. Biol. Interactions, 52, 361-375 (1985); Ito, CRC Crit. Rev. Anal. Chem., 17, 65-143 (1986); Rinehart et al., xe2x80x9cTopics in Pharmaceutical Sciences 1989xe2x80x9d pp. 613-626, D. D. Breimer, D. J. A. Cromwelin, K. K. Midha, Eds., Amsterdam Medical Press B.V., Noordwijk, The Netherlands (1989); Rinehart et al., xe2x80x9cBiological Mass Spectrometry,xe2x80x9d 233-258 eds. Burlingame et al., Elsevier Amsterdam (1990); Guan et al., Jour. Biomolec. Struc and Dynam., vol. 10 pp. 793-817 (1993); Nakagawa et al., J. Amer. Chem. Soc., 111: 2721-2722 (1989); Lichter et al., xe2x80x9cFood and Drugs from the Sea Proceedingsxe2x80x9d (1972), Marine Technology Society, Washington, D.C. 1973, 117-127; Sakai et al., J. Amer. Chem. Soc., 1996, 118, 9017; Garcia-Rocha et al., Brit. J. Cancer, 1996, 73: 875-883; and Pommier et al., Biochemistry, 1996, 35: 13303-13309.
The disclosures of the above-referenced patents and publications are hereby incorporated herein by reference.
Et 743 (NSC 648766) is currently undergoing evaluation by the National Cancer Institute on the basis of exceedingly potent activity in vivo against a variety of tumors. 
In 1996, the total synthesis of Et-743 was reported. See E. J. Corey et al., J. Amer. Chem. Soc., 118, 9292-9203 (1996); see also, U.S. Pat. No. 5,721,362. Disclosed in the ""362 patent is the intermediate 11, with the following structure: 
This intermediate compound, re-designated herein as Compound 1, has served as the starting material for a series of new synthetic ecteinascidin-like compounds.
The present invention is directed to compounds having the following formula 
wherein the substituent groups defined by R1, R2, R3, R4, R5, R6, R7, R8 and R9 are each independently selected from the group consisting of H, OH, ORxe2x80x2, SH, SRxe2x80x2, SORxe2x80x2, SO2Rxe2x80x2, NO2, NH2, NHRxe2x80x2, N(Rxe2x80x2)2, NHC(O)Rxe2x80x2, CN, halogen, xe2x95x90O, C(xe2x95x90O)H, C(xe2x95x90O)Rxe2x80x2, CO2H, CO2Rxe2x80x2, C2-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic;
wherein each of the Rxe2x80x2 groups is independently selected from the group consisting of H, OH, NO2, NH2, SH, CN, halogen, xe2x95x90O, C(xe2x95x90O)H, C(xe2x95x90O)CH3, CO2H, CO2CH3, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, aryl, aralkyl, and heteroaromatic;
wherein each dotted circle represents one, two or three optional double bonds;
wherein R7 and R8 may be joined into a carbocyclic or heterocyclic ring system; and wherein X1 and X2 are each independently defined as above for R1-R8, and further include the definitions of X1 and X2 as provided below for the preferred embodiments.
Preferred compounds of the present invention have the following formula: 
wherein the substituent groups defined by R1, R2, R3, R4, R5, R6, R7, R8 and R9 are each independently selected from the group consisting of H, OH, ORxe2x80x2, SH, SRxe2x80x2, SORxe2x80x2, SO2Rxe2x80x2, NO2, NH2, NHRxe2x80x2, N(Rxe2x80x2)2, NHC(O)Rxe2x80x2, CN, halogen, xe2x95x90O, C1-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic;
wherein each of the Rxe2x80x2 groups is independently selected from the group consisting of H, OH, NO2, NH2, SH, CN, halogen, xe2x95x90O, C(xe2x95x90O)H, C(xe2x95x90O)CH3, CO2H, CO2CH3, C1-C6 alkyl, phenyl, benzyl, and heteroaromatic;
wherein each dotted circle represents one, two or three optional double bonds;
and wherein X1 and X2 are each independently defined as above for R1-R8, and further include the definitions of X1 and X2 as provided below for the preferred embodiments.
Suitable halogen substituents in the compounds of the present invention include F, Cl, Br and I.
Alkyl groups preferably have from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms. Methyl, ethyl and propyl including isopropyl are particularly preferred alkyl groups in the compounds of the present invention. As used herein, the term alkyl, unless otherwise modified, refers to both cyclic and noncyclic groups, although cyclic groups will comprise at least three carbon ring members.
Preferred alkenyl and alkynyl groups in the compounds of the present invention have one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more preferably 2 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. The terms alkenyl and alkynyl as used herein refer to both cyclic and noncyclic groups, although straight or branched noncyclic groups are generally more preferred.
Preferred alkoxy groups in the compounds of the present invention include groups having one or more oxygen linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms.
Preferred alkylthio groups in the compounds of the present invention have one or more thioether linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylthio groups having 1, 2, 3 or 4 carbon atoms are particularly preferred.
Preferred alkylsulfinyl groups in the compounds of the present invention include those groups having one or more sulfoxide (SO) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfinyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred.
Preferred alkylsulfonyl groups in the compounds of the present invention include those groups having one or more sulfonyl (SO2) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred.
Preferred aminoalkyl groups include those groups having one or more primary, secondary and/or tertiary amine groups, and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 21 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. Secondary and tertiary amine groups are generally more preferred than primary amine moieties.
Suitable heteroaromatic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e.g., coumarinyl including 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazol. Suitable heteroalicyclic groups in the compounds of the present invention contain one, two or three, heteroatoms selected from N, O or S atoms and include, e.g., tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl groups.
Suitable carbocyclic aryl groups in the compounds of the present invention include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups. Typical carbocyclic aryl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms. Specifically preferred carbocyclic aryl groups include phenyl including substituted phenyl, such as 2-substituted phenyl, 3-substituted phenyl, 2,3-substituted phenyl, 2,5-substituted phenyl, 2,3,5-substituted and 2,4,5-substituted phenyl, including where one or more of the phenyl substituents is an electron-withdrawing group such as halogen, cyano, nitro, alkanoyl, sulfinyl, sulfonyl and the like; naphthyl including 1-naphthyl and 2-naphthyl; biphenyl; phenanthryl; and anthracyl.
References herein to substituted Rxe2x80x2 groups in the compounds of the present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e.g., halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C1-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having those having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocylic aryl having 6 or more carbons, particularly phenyl (e.g., R being a substituted or unsubstituted biphenyl moiety); and aralkyl such as benzyl.
The compounds of the present invention can be prepared synthetically from the intermediate compound 11 described in the ""362 patent. Numerous active antitumor compounds have been prepared from this compound and it is believed that many more compounds may be formed in accordance with the teachings of the present disclosure.
One especially preferred embodiment of the present invention is the novel ecteinascidin-like compounds that have been prepared from Compound 1: 
wherein X1 and X2 are each independently selected from the group consisting of: 
or the formula: 
wherein Z is selected from the group consisting of: 
wherein each R group, which may be the same or be different, is selected from the group consisting of H, OH, SH, NH2, NO2, CN, NH(Cxe2x95x90O)CH3, O(Cxe2x95x90O)CH3, halogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-acyl, aryl or alkylaryl.
Another especially preferred embodiment of the present invention is pharmaceutical compositions useful as antitumor agents, comprising an effective antitumor amount of one or more of the compounds of the present invention and a pharmaceutically acceptable diluent, carrier or excipient.
Yet another especially preferred embodiment of the present invention is the synthetic intermediates of the compounds of the present invention as described in detail below.
Finally, the present invention includes the synthetic processes described herein.
The currently most preferred compound of the present invention is the compound of formula 7: 
The preferred method of producing the compound of formula 7 is set forth below in Scheme I: 
As illustrated in Scheme I, the first step for producing the preferred compound 7 of the present invention is the high yield conversion (93%) of the phenol compound 1 to the allyl ether compound 2. The second step is the high yield (99%) removal of the TBDPS protecting group to form the free alcohol compound 3. The third step in this process is the high yield (91%) coupling of phthalimide to the free alcohol compound 3 to yield the phthalimide derivative, compound 4. The phthalimide compound 4 is then converted in high yield (97%) to the phenol compound 5. Phenol compound 5 is converted in high yield (94%) to the methoxymethyl ether compound 6. Alternatively, the phthalimide compound 4 can be treated with several reagents to produce in high yield (91%) the methoxymethyl ether compound 6. The methoxymethyl ether compound 6 is finally reacted with trifluoroacetic acid to provide the desired compound 7, in high yield (94%). The overall yield of this process is about 72%.
The Scheme I method can be modified for the preparation of a preferred group of compounds. This modification is shown below in Scheme II: 
In Scheme II, the free alcohol compound 3 is protected by reaction with 2-methoxypropene to yield the allyl ether compound 8 in high yield (99%). Compound 8 is then converted into the intermediate alcohol 9 in three steps with an overall yield of 89%. Compound 9 can be reacted with a wide variety of phthalimides, dicarboximides, or equivalents thereof (e.g., amides, including aromatic amides, ureas, urethanes, sulfonamides, alkoxy compounds, urethanes, and the like) to form compounds of the formula: 
wherein X1 is the radical provided by the phthalimide, dicarboximide or equivalent compound. Especially preferred compounds prepared by the Scheme II process include the compounds wherein X1 has the formula: 
and wherein Z is selected from the group consisting of: 
wherein each R group, which may be the same or be different, is selected from the group consisting of hydrogen, amino, halogen, nitro, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-acyl, aryl, especially phenyl or alkylaryl, especially benzyl.
In yet another preferred modification, the phenol compound 5 may be transformed into a number of derivatives, as shown in Scheme III: 
As shown in Scheme III, the phenol compound (5) is reacted with various side-chain modifying carboxylic acids to afford the corresponding phenolic esters. Scheme III can be used to produce numerous compounds having the formula: 
wherein X2 is the radical provided by the carboxylic acid. Especially preferred X2 groups are selected from the group consisting of: 
Another modification is the alkylation reaction illustrated in Scheme IV: 
In Scheme IV, the phenol compound 5 is treated with an alkylating agent to afford the corresponding R4 derivatives. Scheme IV can be used to produce numerous compounds having the formula: 
wherein X2 is the radical provided by the alkylating agent. Representative derivatives of this type include the compounds wherein X2 is selected from the group consisting of: 
Several key intermediate compounds include the tosylate 29, the azide compound 30, and the free amine compound 31. The reaction sequence for these compounds is shown below in Scheme V: 
The following additional compounds of the present invention (including for example, Compounds 43, 44, 45, 46, 47, 48, 49, 50, 51, 54, 55 and 56) have been prepared as described in detail in the Examples infra: 
As the skilled artisan will readily appreciate, the reaction schemes described herein may be modified and/or combined in various ways, and the compounds generated therefrom are to be considered as being part of this invention.